Currently, HMG-CoA reductase inhibitors (statins) are the primary drugs to treat hypercholesterolemia. This class of drugs potently lowers serum LDL-cholesterol mainly through increased hepatic LDL receptor (LDLR) expression by activation of LDLR transcription. Statins effectively reduce elevated LDL-c and lessen the risk of coronary heart disease and related cardiovascular events. However, despite the success with statin treatments, a significant number of hypercholesterolemic patients do not achieve an acceptable plasma cholesterol level by a single drug therapy, and some patients do not tolerate statins owing to symptoms of muscle pain and muscle weakness caused by statins dose-dependently. Thus, in these cases, combination therapy by two agents with different modes of action might result in a better cholesterol-lowering effect with an improved efficacy of statins. We have identified Berberine (BBR), a compound originally isolated from the Chinese herb Hunglian as a novel upregulator of hepatic LDLR. We demonstrated that BBR strongly increased the hepatic LDLR expression by increasing the LDLR mRNA stability. We also demonstrated the effectiveness of BBR in reducing plasma cholesterol and LDL-c in hypercholesterolemic patients without side effects in a placebo-controlled clinical study. Recently, we have further identified that the BBR-containing medicinal plant extract goldenseal is a potent lipid-lowering natural product. Goldenseal strongly increases LDLR expression in HepG2 cells and effectively lowers plasma cholesterol and LDL-c in hyperlipidemic hamsters. Based upon these mechanistic and clinical studies, we hypothesize that BBR and its natural product goldenseal are promising candidates for statin combination therapy in treating hypercholesterolemic patients. The overall objectives of this new R21 proposal are to explore potential applications of the pure compound BBR and the crude extract goldenseal in combination therapy with current cholesterol lowering drug statins. The specific aims of this new proposal are to: 1) Use the human ApoB/CETP double trasnsgenic mice, which have a lipid profile similar to humans, as an vivo animal model to determine if the herbal medicine goldenseal or the pure compound BBR is capable of potentiating the lipid lowering effects of fluvastatin and ameliorating the side effects of fluvastatin in damaging hepatic functions;and 2) We will examine the effects of BBR and goldenseal on fluvastatin pharmacokinetics to determine whether drug interactions occur in animals co-administered with statin and BBR. These proposed studies are exploratory and highly innovative. The success of these studies will ultimately benefit patients by offering more choices for their individual needs in reducing plasma cholesterol levels to prevent atherosclerotic cardiovascular disease.